Recent evidence has clearly shown that cytokines can suppress experimental allergic encephalomyelitis (EAE), a rodent model of central nervous system (CNS) autoimmune disease. These cytokines influence the activation and/or expansion of the Th1 effector subset of CD4+ T cells which not only induce EAE but are the effectors of a number of autoimmune diseases. This proposal is based on differential CD4+ responses induced in EAE susceptible female (Th1 responsiveness) and EAE resistant male SJL mice (Th2 responsiveness). This dichotomy of female susceptibility is consistent with the increased prevalence of a number of human autoimmune diseases including multiple sclerosis, myasthenia gravis, rheumatoid arthritis and SLE in females. Thus, the sex-based difference in CD4+ T cell responsiveness in SJL mice provides the unique opportunity to explore induction and suppression of Th1 and Th2 cells in an in vivo model using a single mouse strain. Adoptive transfer of a mixture of myelin basic protein-specific Th1 effector/Th2 suppressor cells into EAE susceptible mice has a dramatic suppressive effect on EAE compared to recipients of Th1 effectors only. This proposal determines both the constraints imposed on Th2-mediated EAE suppression and if Th2 cells must access the target organ to suppress disease. Another novel aspect of this model is that Th2 responses in EAE resistant male mice are reversed to Th1 responses via adoptive transfer of an antigen presenting cell (APC) subset derived from EAE susceptible female mice. The mechanism of APC-dependent CD4+ T cell polarization is examined by monoclonal antibody-mediated ablation of Th2 cytokines (IL-4 and IL-10) and increases in Th1 cytokines (IL-12 and IFN-gamma) using recombinant cytokine. A direct effect on APC-dependent priming versus expansion of EAE effectors will be determined by examining phenotype changes in APC derived from cytokine treated males exhibiting the EAE susceptible phenotype. This proposal explores the basis for APC-dependent in vivo regulation of Th1/Th2 priming to self antigens, which plays a determinant role in the outcome of a number of autoimmune diseases. Information on the induction and regulation of Th1/Th2 cells may provide a viable alternative for cytokine-based immunotherapies and suggest the possibility that induction or transfer of autologous Th2 cells may be useful in ameliorating autoimmune disease.